Source: Υπουργείο Υγείας (CY) Revision Year: 2023 Publisher: Sanofi Winthrop Industrie, 82 avenue Raspail, 94250 Gentilly, France
Depakine Chrono is contraindicated in the following situations:
Stopping treatment may lead to an immediate relapse of the underlying symptoms; care should therefore be taken when consideration is being given to the withdrawal of treatment.
Severe liver damage, including hepatic failure sometimes resulting in fatalities, has been exceptionally reported.
Experience in epilepsy has indicated that patients most at risk, especially in cases of multiple anticonvulsant therapy, are infants and in particular young children under the age of 3 and those with severe seizure disorders, organic brain disease, and (or) congenital metabolic or degenerative disease associated with mental retardation.
After the age of 3, the incidence of occurrence is significantly reduced and progressively decreases with age.
In most cases, such liver damage occurred during the first 6 months of therapy, the period of maximum risk being 2-12 weeks.
Clinical symptoms are essential for early diagnosis. In particular, the following conditions, which may precede jaundice, should be taken into consideration, especially in patients at risk (see above: ‘Conditions of occurrence’):
These are an indication for immediate withdrawal of the drug.
Patients (or their family for children) should be instructed to report immediately any such signs to a physician should they occur. Investigations including clinical examination and biological assessment of liver function should be undertaken immediately.
Liver function tests should be performed before therapy and then periodically during the first 6 months of therapy, especially for patients at risk. Upon changes in concomitant medicinal products (dose increase or additions) that are known to impact the liver, liver monitoring should be restarted as appropriate (see also section 4.5 on risk of liver damage with salicylates, other anticonvulsants including cannabidiol).
Amongst usual investigations, tests which reflect protein synthesis, particularly prothrombin rate, are most relevant.
Confirmation of an abnormally low prothrombin rate, particularly in association with other biological abnormalities (significant decrease in fibrinogen and coagulation factors; increased bilirubin level and raised transaminases) requires cessation of Depakine therapy.
As a matter of precaution and in case they are taken concomitantly salicylates should also be discontinued since they employ the same metabolic pathway.
Severe pancreatitis, which may result in fatalities, has been very rarely reported. Patients experiencing acute abdominal pain should have a prompt medical evaluation. Young children are at particular risk; this risk decreases with increasing age. Severe seizures and severe neurological impairment with combination anticonvulsant therapy may be risk factors. Hepatic failure with pancreatitis increases the risk of fatal outcome. Pancreatitis experiencing acute abdominal pain should have a prompt medical evaluation. In case of pancreatitis, valproate should be discontinued.
Valproate has a high teratogenic potential and children exposed in utero to valproate have a high risk for congenital malformations and neurodevelopmental disorders (see section 4.6).
Depakine Chrono is contraindicated in the following situations:
Treatment of epilepsy:
Treatment of bipolar disorder:
Conditions of Pregnancy Prevention Program:
The prescriber must ensure that:
These conditions also concern women who are not currently sexually active unless the prescriber considers that there are compelling reasons to indicate that there is no risk of pregnancy.
Pregnancy must be excluded before start of treatment with valproate. Treatment with valproate must not be initiated in women of child-bearing potential without a negative pregnancy test (plasma pregnancy test) result, confirmed by a health care provider, to rule out unintended use in pregnancy.
Women of childbearing potential who are prescribed valproate must use effective contraception, without interruption during the entire duration of treatment with valproate. These patients must be provided with comprehensive information on pregnancy prevention and should be referred for contraceptive advice if they are not using effective contraception. At least one effective method of contraception (preferably a user independent form such as an intra-uterine device or implant) or two complementary forms of contraception including a barrier method should be used. Individual circumstances should be evaluated in each case, when choosing the contraception method involving the patient in the discussion, to guarantee her engagement and compliance with the chosen measures. Even if she has amenorrhea, she must follow all the advice on effective contraception.
Concomitant use with estrogen-containing products, including estrogen-containing hormonal contraceptives, may potentially result in decreased valproate efficacy (see section 4.5). Prescribers should monitor clinical response (seizure control or mood control) when initiating or discontinuing estrogen-containing products.
On the opposite, valproate does not reduce efficacy of hormonal contraceptives.
The specialist should at least annually review whether valproate is the most suitable treatment for the patient. The specialist should discuss the annual risk acknowledgement form, at initiation and during each annual review and ensure that the patient has understood its content.
For the indication epilepsy, if a woman is planning to become pregnant, a specialist experienced in the management of epilepsy, must reassess valproate therapy and consider alternative treatment options. Every effort should be made to switch to appropriate alternative treatment prior to conception, and before contraception is discontinued (see section 4.6). If switching is not possible, the woman should receive further counselling regarding the valproate risks for the unborn child to support her informed decision-making regarding family planning.
For the indication bipolar disorder, if a woman is planning to become pregnant a specialist experienced in the management of bipolar disorder must be consulted and treatment with valproate should be discontinued and if needed switched to an alternative treatment prior to conception, and before contraception is discontinued.
If a woman using valproate becomes pregnant, she must be immediately referred to a specialist to re-evaluate treatment with valproate and consider alternative options. The patients with a valproate exposed pregnancy and their partners should be referred to a specialist experienced in teratology for evaluation and counselling regarding the exposed pregnancy (see section 4.6).
In order to assist healthcare professionals and patients in avoiding exposure to valproate during pregnancy, the Marketing Authorisation Holder has provided educational materials to reinforce the warnings and provide guidance regarding use of valproate in women of childbearing potential and the details of the pregnancy prevention program. A patient guide and patient card should be provided to all women of childbearing potential using valproate.
An annual risk acknowledgement form needs to be used at time of treatment initiation and during each annual review of valproate treatment by the specialist.
Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomised placebo-controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known, and the available data do not exclude the possibility of an increased risk for valproate.
Therefore, patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
The concomitant use of Depakine Chrono and carbapenem agents is not recommended (see Section 4.5).
Valproate may trigger or worsen clinical signs of underlying mitochondrial diseases caused by mutations of mitochondrial DNA as well as the nuclear encoded POLG gene. In particular, valproate-induced acute liver failure and liver-related deaths have been reported at a higher rate in patients with hereditary neurometabolic syndromes caused by mutations in the gene for the mitochondrial enzyme polymerase γ (POLG), e.g. Alpers-Huttenlocher Syndrome.
POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders (see section 4.3).
As with other antiepileptic drugs, some patients may experience, instead of an improvement, a reversible worsening of convulsion frequency and severity (including status epilepticus), or the onset of new types of convulsions with valproate. In case of aggravated convulsions, the patients should be advised to consult their physician immediately (see Section 4.8).
Liver function tests should be carried out before therapy (see section 4.3 Contraindications), and periodically during the first 6 months, especially in patients at risk (see section 4.4 Special warnings).
As with most antiepileptic drugs, a slight increased liver enzymes are common, particularly at the beginning of therapy; they are transient and isolated.
More extensive biological investigations (including prothrombin rate) are recommended in these patients; a reduction in dosage may be considered when appropriate and tests should be repeated as necessary.
Haematological: Blood tests (blood cell count, including platelet count, bleeding time and coagulation tests) are recommended prior to initiation of therapy or before surgery, and in case of spontaneous bruising or bleeding (see section 4.8).
Systemic lupus erythematosus: Although immune disorders have only rarely been noted during the use of Depakine, the potential benefit of Depakine should be weighed against its risk in patients with systemic lupus erythematosus (see also section 4.8).
Hyperammonaemia: When a urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment because of the risk of hyperammonaemia with valproate (see section 4.3).
Weight gain: Patients should be warned of the risk of weight gain at the initiation of therapy and appropriate strategies should be adopted to minimise it (see 4.8)
Patients with an underlying carnitine palmitoyltransferase (CPT) type II deficiency should be warned of the greater risk of rhabdomyolysis when taking valproate.
Alcohol: Alcohol intake is not recommended during treatment with valproate.
Children: Monotherapy is recommended in children under the age of 3 years when prescribing valproate, but the potential benefit of valproate should be weighed against the risk of liver damage or pancreatitis in such patients prior to initiation of therapy (see section 4.4 Severe liver damage and see also section 4.5).
The concomitant use of salicylates should be avoided in children under 3 years of age due to the risk of liver toxicity (see also section 4.5).
Renal insufficiency: In patients with renal insufficiency, it may be necessary to decrease dosage. As monitoring of plasma concentrations may be misleading, dosage should be adjusted according to clinical monitoring (see sections 4.2 and 5.2.).
Diabetic patients: Since valproate is excreted mainly through the kidneys partly in the form of ketone bodies; ketone body excretion test may give false positive results in diabetic patient.
Depakine may potentiate the effect of other psychotropics such as neuroleptics, MAO inhibitors, antidepressants and benzodiazepines; therefore, clinical monitoring is advised and dosage should be adjusted when appropriate.
In particular, a clinical study has suggested that adding olanzapine to valproate therapy may significantly increase the risk of certain adverse events associated with olanzapine.
Depakine Chrono has no effect on serum lithium levels.
Depakine increases phenobarbital plasma concentrations (due to inhibition of hepatic catabolism) and sedation may occur, particularly in children. Therefore, clinical monitoring is recommended throughout the first 15 days of combined treatment with immediate reduction of phenobarbital doses if sedation occurs and determination of phenobarbital plasma levels when appropriate.
Depakine increases primidone plasma levels with exacerbation of its adverse effects (such as sedation); these signs cease with long-term treatment. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.
Depakine decreases phenytoin total plasma concentration. Moreover, Depakine increases phenytoin free form with possible overdose symptoms (valproic acid displaces phenytoin from its plasma protein binding sites and reduces its hepatic catabolism). Therefore, clinical monitoring is recommended; when phenytoin plasma levels are determined, the free form should be evaluated.
Clinical toxicity has been reported when valproate was administered with carbamazepine as valproate may potentiate toxic effect of carbamazepine. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.
Depakine Chrono reduces the metabolism of lamotrigine and increases the lamotrigine mean half-life by nearly two-fold. This interaction may lead to increased lamotrigine toxicity, in particular serious skin rashes. Therefore, clinical monitoring is recommended, and dosages should be adjusted (lamotrigine dosage decreased) when appropriate.
Valproate may raise zidovudine plasma concentration leading to increase zidovudine toxicity.
Valproic acid may decrease the felbamate mean clearance by up to 16%.
Valproic acid may decrease the olanzapine plasma concentration.
Valproic acid may lead to an increase in plasma level of rufinamide. This increase is dependent on concentration of valproic acid. Caution should be exercised, in particular in children, as this effect is larger in this population.
Valproic acid may lead to an increased blood level of propofol. When co-administered with valproate, a reduction of the dose of propofol should be considered.
In patients concomitantly treated with sodium valproate and nimodipine the exposure to nimodipine can be increased by 50%. The nimodipine dose should therefore be decreased in case of hypotension.
The anticoagulant effect of warfarin and other coumarin anticoagulants may be increased following displacement from plasma protein binding sites by valproic acid. The prothrombin time should be closely monitored.
Antiepileptics with enzyme inducing effect (including phenytoin, phenobarbital, carbamazepine) decrease valproic acid serum concentrations. Dosages should be adjusted according to clinical response and blood levels in case of combined therapy.
On the other hand, combination of felbamate and valproate decrease valproic acid clearance by 22% to 50%, and consequently increase the valproic acid plasma concentration. Valproate dosage should be monitored.
Valproic acid serum levels may be increased in case of concomitant use with phenytoin or phenobarbital. Therefore, patients treated with those two drugs should be carefully monitored for signs and symptoms of hyperammonemia.
Mefloquine and chloroquine increase valproic acid metabolism and has a convulsing effect; therefore, epileptic seizures may occur in cases of combined therapy.
The dosage of Depakine Chrono may need adjustment accordingly.
In case of concomitant use of valproate and highly protein bound agents (aspirin), valproic acid free serum levels may be increased.
Close monitoring of prothrombin rate should be performed in case of concomitant use of vitamin K dependent factor anticoagulant.
Valproic acid serum levels may be increased (as a result of reduced hepatic metabolism) in case of concomitant use with cimetidine or erythromycin.
Decrease in blood levels of valproic acid have been reported when it is co-administered with carbapenem agents resulting in a 60-100% decrease in valproic acid level in about two days. Due to the rapid onset and the extent of the decrease, co-administration of carbapenem agents in patients stabilised in valproic acid is not considered to be manageable and therefore should be avoided (see section 4.4).
Colestyramine may lead to a decrease in plasma level of valproate when co-administered.
Rifampicin may decrease the valproic acid blood levels resulting in a lack of therapeutic effect. Therefore, valporate dosage adjustment may be necessary when it is co-administered with rifampicin.
Protease inhibitors such as lopinavir, ritobavir, decrease valproate plasma level when co-administered.
Estrogens are inducers of the UDP-glucuronosyl transferase (UGT) isoforms involved in valproate glucuronidation and may increase the clearance of valproate, which would result in decreased serum concentration of valproate and potentially decreased valproate efficacy (see section 4.4). Consider monitoring of valproate serum levels.
On the opposite, valproate has no enzyme inducing effect; as a consequence, valproate does not reduce efficacy of oestroprogestative agents in women receiving hormonal contraception.
Metamizole may decrease valproate serum levels when co-administered, which may result in potentially decreased valproate clinical efficacy. Prescribers should monitor clinical response (seizure control or mood control) and consider monitoring valproate serum levels as appropriate.
The concomitant use of salicylates should be avoided in children under 3 years of age due to the risk of liver toxicity (see section 4.4).
Concomitant use of valproate and multiple anticonvulsant therapy increases the risk of liver damage, especially in young children (see section 4.4).
Concomitant use with cannabidiol increases the incidence of transaminases enzyme elevation. In clinical trials in patients of all ages receiving concomitantly cannabidiol at doses 10 to 25 mg/kg and valproate, ALT increases greater than 3 times the upper limit of normal have been reported in 19% of patients. Appropriate liver monitoring should be exercised when valproate is concomitantly used with other anticonvulsants with potential hepatotoxicity, including cannabidiol, and dose reductions or discontinuation should be considered in case of significant anomalies of liver parameters (see section 4.4).
Caution is advised when using Depakine in combination with newer antiepileptics whose pharmacodynamics may not be well established.
Concomitant administrations of valporate and topiramate or acetazolamide has been associated with encephalopathy and/or hyperammonemia. Patients treated with those two drugs should be carefully monitored for signs and symptoms of hyperammonemic encephalopathy.
Co-administration of valproate and quetiapine may increase the risk of neutropenia/leucopenia.
Valproate usually has no enzyme inducing effect; as a consequence, valproate does not reduce efficacy of estroprogestative agents in women receiving hormonal contraception.
Valproate is contraindicated as treatment for bipolar disorder during pregnancy. Valproate is contraindicated as treatment for epilepsy during pregnancy unless there is no suitable alternative to treat epilepsy. Valproate is contraindicated for use in women of childbearing potential unless the conditions of the pregnancy prevention programme are fulfilled (see sections 4.3 and 4.4).
Depakine Chrono should not be used in female children, in female adolescents, in women of childbearing potential and in pregnant women unless other treatments are ineffective or not tolerated. Women of childbearing potential have to use effective contraception during treatment. In women planning to become pregnant all efforts should be made to switch to appropriate alternative treatment prior to conception, if possible.
From experience in treating mothers with epilepsy, the risk associated with the use of Depakine during pregnancy has been described as follows:
During pregnancy, maternal tonic clinic seizures and status epile pticus with hypoxia carry a particular risk of death for mother and for the unborn child.
Congenital malformations:
A meta-analysis (including registries and cohort studies) showed that about 11 % of children of epileptic women exposed to valproate monotherapy during pregnancy had major congenital malformations. This is greater than the risk of major malformations in the general population (about 2-3%).
The risk of major congenital malformations in children after in utero exposure to antiepileptic drug polytherapy including valproate is higher than that of anti-epileptic drugs polytherapy not including valproate.
This risk is dose dependent in valproate monotherapy, and available data suggest it is dose-dependent in valproate polytherapy. However, a threshold dose below which no risk exists cannot be established.
Available data show an increased incidence of minor and major malformations. The most common types of malformations include neural tube defects, facial dysmorphism, cleft lip and palate, craniostenosis, cardiac, renal and urogenital defects, limb defects (including bilateral aplasia of the radius), and multiple anomalies involving various body systems.
In utero exposure to valproate may also result in hearing impairment/loss or deafness due to ear and/or nose malformations (secondary effect) and/or to direct toxicity on the hearing function. Cases describe both unilateral and bilateral deafness or hearing impairment. Outcomes were not reported for all cases. When outcomes were reported, the majority of the cases did not recover.
In utero exposure to valproate may result in eye malformations (including colobomas, microphthalmos) that have been reported in conjunction with other congenital malformations. These eye malformations may affect vision.
Both valproate monotherapy and valproate polytherapy, including other antiepileptics, are frequently associated with abnormal pregnancy outcomes. Available data show an increased risk of major congenital malformations and neurodevelopmental disorders in both valproate monotherapy and polytherapy compared to the population not exposed to valproate.
Valproate was shown to cross the placental barrier both in animal species and in humans (see section 5.2).
In animals: teratogenic effects have been demonstrated in mice, rats and rabbits (see section 5.3).
Data have shown that exposure to valproate in utero can have adverse effects on mental and physical development of the exposed children. The risk of neurodevelopmental disorders (including that of autism) seems to be dose-dependent but a threshold dose below which no risk exists cannot be established based on available data. When valproate is administered in polytherapy with other anti-epileptic drugs during pregnancy, the risks of neurodevelopment disorders in the offspring were also significantly increased as compared with those in children from general population or born to untreated epileptic mothers.
The exact gestational period of risk for these effects is uncertain and the possibility of a risk throughout the entire pregnancy cannot be excluded.
When valproate is administered in monotherapy, studies in preschool children exposed in utero to valproate show that up to 30-40% experience delays in their early development such as talking and walking later, lower intellectual abilities, poor language skills (speaking and understanding) and memory problems.
Intelligence quotient (IQ) measured in school aged children (age 6) with a history of valproate exposure in utero was on average 7-10 points lower than those children exposed to other antiepileptics. Although the role of confounding factors cannot be excluded, there is evidence in children exposed to valproate that the risk of intellectual impairment may be independent from maternal IQ.
There are limited data on the long-term outcomes.
Available data from a population-based study show that children exposed to valproate in utero are at increased risk of autistic spectrum disorder (approximately 3-fold) and childhood autism (approximately 5-fold) compared to the unexposed population in the study.
Available data from another population-based study show that children exposed to valproate in utero are at increased risk of developing attention deficit/hyperactivity disorder (ADHD) (approximately 1.5-fold) compared to the unexposed population in the study.
For the indication epilepsy, if a woman is planning to become pregnant, a specialist experienced in the management of epilepsy, must reassess valproate therapy and consider alternative treatment options. Every effort should be made to switch to appropriate alternative treatment prior to conception, and before contraception is discontinued (see section 4.4). If switching is not possible, the woman should receive further counselling regarding the valproate risks for the unborn child to support her informed decision-making regarding family planning.
For the indication bipolar disorder, if a woman is planning to become pregnant a specialist experienced in the management of bipolar disorder must be consulted and treatment with valproate should be discontinued and if needed switched to an alternative treatment prior to conception, and before contraception is discontinued.
Valproate as treatment for bipolar disorder is contraindicated for use during pregnancy.
Valproate as treatment for epilepsy is contraindicated in pregnancy unless there is no suitable alternative treatment (see sections 4.3 and 4.4).
If a woman using valproate becomes pregnant, she must be immediately referred to a specialist to consider alternative treatment options. During pregnancy, maternal tonic clonic seizures and status epilepticus with hypoxia may carry a particular risk of death for mother and the unborn child.
If, despite the known risks of valproate in pregnancy and after careful consideration of alternative treatment, in exceptional circumstances a pregnant woman must receive valproate for epilepsy, it is recommended to:
All patients with a valproate exposed pregnancy and their partners should be referred to a specialist experienced in teratology for evaluation and counselling regarding the exposed pregnancy. Specialized prenatal monitoring should take place to detect the possible occurrence of neural tube defects or other malformations. Folate supplementation before the pregnancy may decrease the risk of neural tube defects which may occur in all pregnancies. However, the available evidence does not suggest it prevents the birth defects or malformations due to valproate exposure.
Estrogen-containing products
Estrogen-containing products, including estrogen-containing hormonal contraceptives, may increase the clearance of valproate, which would result in decreased serum concentration of valproate and potentially decreased valproate efficacy (sections 4.4 and 4.5).
If a Woman wants to plan a Pregnancy:
Valproate therapy should not be discontinued without a reassessment of the benefits and risks of the treatment with valproate for the patient by a physician experienced in the management of epilepsy or bipolar disorder. If based on a careful evaluation of the risks and the benefits valproate treatment is continued during the pregnancy, it is recommended to:
Cases of haemorrhagic syndrome have been reported very rarely in neonates whose mothers have taken valproate during pregnancy. This haemorrhagic syndrome is related to thrombocytopenia, hypofibrinogenemia and/or to decrease in other coagulation factors. Afibrinogenemia has also been reported and may be fatal. However, this syndrome has to be distinguished from the decrease of the vitamin-K factors induced by phenobarbital and enzymatic inducers.
Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates.
Cases of hypoglycaemia have been reported in neonates whose mothers have taken valproate during the third trimester of the pregnancy.
Cases of hypothyroidism have been reported in neonates whose mothers have taken valproate during pregnancy.
Withdrawal syndrome (such as, in particular, agitation, irritability, hyper-excitability, jitteriness, hyperkinesia, tonicity disorders, tremor, convulsion and feeding disorders) may occur in neonates whose mothers have taken valproate during the last trimester of pregnancy.
Valproate is excreted in human milk with a concentration ranging from 1% to 10% of maternal serum levels. Hematological disorders have been shown in breastfed newborns/infants of treated women (see section 4.8).A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Depakine Chrono therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Amenorrhoea, polycystic ovaries and increased testosterone levels have been reported in women using valproate (see section 4.8).
Valproate administration may also impair fertility in men (see section 4.8). Fertility dysfunctions are in some cases reversible at least 3 months after treatment discontinuation. Limited number of case reports suggest that a strong dose reduction may improve fertility function. However, in some other cases, the reversibility of male infertility was unknown.
The patient should be warned of the risk of somnolence especially in cases of anticonvulsant polytherapy or association with benzodiazepines (see section 4.5).
The following CIOMS frequency rating is used, when applicable: Very common ≥10%; Common ≥1 and <10%; Uncommon ≥0.1 and <1%; Rare ≥0.01 and <0.1%; Very rare <0.01%, Unknown (cannot be estimated from available data).
Congenital malformations and developmental disorders (see section 4.4 and section 4.6).
Common: anaemia, thrombocytopenia
Uncommon: pancytopenia, leucopenia
Rare: bone marrow failure, including pure red cell aplasia, agranulocytosis, anaemia macrocytic, macrocytosis.
Rare: coagulation factors decreased (at least one), abnormal coagulation tests (such as prothrombin time prolonged, activated partial thromboplastin time prolonged, thrombin time prolonged, INR prolonged) (see § 4.4 “Special warnings and precautions for use” and § 4.6. “Pregnancy”), biotin deficiency/biotinidase deficiency.
Very common: tremor, sedation
Common: extrapyramidal disorder, stupor*, somnolence, convulsion*, memory impairment, headache, nystagmus, dizziness
Uncommon: coma*, encephalopathy*, lethargy* (see below), reversible Parkinsonism, ataxia, paresthesia, aggravated convulsions (see Section 4.4).
Rare: reversible dementia associated with reversible cerebral atrophy, cognitive disorder, diplopia.
Stupor and lethargy sometimes leading to transient coma/encephalopathy they were isolated or associated with an increase in the occurrence of convulsions whilst on therapy and they decreased on withdrawal of treatment or reduction of dosage. These cases mostly occurred during combined therapy (in particular with Phenobarbital or topiramate) or after a sudden increase in valproate doses.
Common: deafness.
Uncommon: pleural effusion.
Very common: nausea*
Common: vomiting, gingival disorder (mainly gingival hyperplasia), stomatitis, abdominal pain upper, diarrhea, frequently occur in some patients at the start of treatment, but they usually disappear after a few days without discontinuing the treatment.
* Also observed a few minutes after intravenous injection with spontaneous resolution within a few minutes.
Uncommon: pancreatitis, sometimes lethal, (see. § 4.4 Special Warnings and Special Precautions for Use).
Common: urinary incontinence
Uncommon: renal failure
Rare: enuresis, tubulointerstitial nephritis, reversible Fanconi’s syndrome but the mode of action is as yet unclear.
Common: hypersensitivity, transient and/or dose related alopecia, nail and nail bed disorders.
Uncommon: angioedema, rash, hair disorder (such as hair texture abnormal, hair colour changes, hair growth abnormal).
Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, Drug
Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome.
Uncommon: bone mineral density decreased, osteopenia, osteoporosis and fractures in patients on long-term therapy with Depakine Chrono. The mechanism by which Depakine Chrono affect bone metabolism has not been identified.
Rare: systemic lupus erythematosus (see. § 4.4 Special Warnings and Special Precautions for Use), rhabdomyolysis (see. § 4.4 Special Warnings and Special Precautions for Use),
Uncommon: Syndrome of Inappropriate Secretion of ADH (SIADH), hyperandrogenism (hirsutism, virilism, acnewa, male pattern alopecia and/or androgen increased)
Rare: hypothyroidism (see § 4.6. “Pregnancy”).
Common: hyponatraemia, weight increased
* Weight increase should be carefully monitored since it is a factor for polycystic ovary syndrome (see § 4.4 “Special warnings and precautions for use”).
Rare: hyperammonaemia*, obesity
* Cases of isolated and moderate hyperammonemia without change in liver function tests may occur and should not cause treatment discontinuation. Hyperammonemia associated with neurological symptoms has also been reported. In such cases, further investigations should be considered (see. § 4.4 Special Warnings and Special Precautions for Use).
Rare: myelodysplastic syndrome.
Common: haemorrhage
Uncommon: vasculitis.
Uncommon: hypothermia, non-severe oedema peripheral
Common: liver injury (see § 4.4.1. “Warnings”)
Common: dysmenorrheal.
Uncommon: amenorrhea
Rare: male infertility (see section 4.6), polycystic ovaries.
Very rare: gynecomastia
Common: confusional state, hallucinations, aggression*, agitation*, disturbance in attention*
Rare: abnormal behaviour*, psychomotor hyperactivity*, learning disorder*.
* These ADRs are principally observed in the paediatric population.
The safety profile of valproate in the paediatric population is comparable to adults, but some ADRs are more severe or principally observed in the paediatric population. There is a particular risk of severe liver damage in infants and young children especially under the age of 3 years. Young children are also at particular risk of pancreatitis. These risks decrease with increasing age (see Section 4.4). Psychiatric disorders such as aggression, agitation, disturbance in attention, abnormal behaviour, psychomotor hyperactivity and learning disorder are principally observed in the paediatric population.
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system: Pharmaceutical Services, Ministry of Health, CY 1475, Nicosia, Tel: +357 22608607, Fax: +357 22608669, Website: www.moh.gov.cy/phs.
Not applicable.
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